Drug addiction is characterized by a high vulnerability to relapse, even following extended drug abstinence. Relapse vulnerability has been linked to dysregulation in nucleus accumbens synaptic function, including altered AMPA glutamate receptor expression. However, the underlying mechanisms of drug-induced changes in accumbens synaptic plasticity are not fully known. Recently, the cell adhesion molecule beta3 integrin was identified as playing a key role in maintaining surface expression of AMPA receptors containing the GluR2 subunit. Data from our laboratory show that chronic intra-accumbens infusion of beta3 integrin modulators to rats during cocaine self-administration reduced subsequent reinstatement of drug-seeking elicited by a cocaine prime and prevented cocaine-induced reductions in GluR2 surface expression. The current proposal is aimed at further elucidating this beta3 integrin signaling pathway to determine the molecular mechanisms of cocaine- induced AMPA receptor changes. I hypothesize that normal beta3 integrin signaling is disrupted by cocaine- induced overactivity of matrix metalloproteinases (MMPs), which causes beta3 integrin-mediated endocytosis of GluR2-containing AMPA receptors via activation of Rap1 intracellular signaling. Specific Aim 1: Using the self-administration model in rats, I first plan to determine whether intra-accumbens core infusions of MMP or Rap1 inhibitors reduce reinstatement of extinguished cocaine-seeking, as seen previously for beta3 integrin modulators. Specific Aim 2: Using the treatment doses found to be most effective for reducing reinstatement behavior, I plan next to evaluate the biochemical consequences of each intra-accumbens treatment (MMP inhibition, Rap1 inhibition, or beta3 integrin modulation). Analyses of accumbens protein expression levels will help reveal the underlying mechanisms of the behavioral effects and possible interactions among components within the hypothesized pathway. Results from these behavioral and biochemical studies will shed light on the molecular mechanisms of cocaine-induced neuroadaptations in accumbens glutamate transmission. PUBLIC HEALTH RELEVANCE: Drug addiction is associated with long-lasting brain changes that cause heightened relapse vulnerability, even after extended drug abstinence. This research study will investigate a molecular signaling pathway that might underlie cocaine-induced changes in synaptic function in nucleus accumbens, a brain structure critically involved in reward learning and addiction. Determining the processes involved in the development of addiction may lead to novel therapeutic options aimed at reversing drug-induced alterations.